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| United States Patent |
6,072,073
|
|
Kawatsura
, et al.
|
June 6, 2000
|
Carbonyl arylations and vinylations using transition metal catalysts
Abstract
The invention is directed to a process for preparing an alpha-arylated or
vinylated carbonyl-containing compounds, comprising reacting a compound
having a carbonyl group with an arylating or vinylating compound in the
presence of a base and a transition metal catalyst. The transition metal
catalyst has the formula X.sub.n M(ER.sub.1-4).sub.m, wherein X is an
optional ligand, M is a group 8 transition metal, E is an element bearing
a nonbonding electron pair when E is not bonded to the metal, and R is a
substituent bonded to E through a carbon, nitrogen, oxygen, or sulfur
atom, with the proviso that R.sub.3 cannot contain 3 aryl groups, n is an
integer from 0 to 4, and m is an integer from 1-4. The process of the
invention is useful for preparation of alpha-arylated or vinylated
carbonyl-containing compounds which are significant in the development of
pharmacologically active compounds and polymers and oligomers.
| Inventors:
|
Kawatsura; Motoi (New Haven, CT);
Hartwig; John F. (New Haven, CT)
|
| Assignee:
|
Yale University (New Haven, CT)
|
| Appl. No.:
|
376898 |
| Filed:
|
August 18, 1999 |
| Current U.S. Class: |
560/82; 558/371; 560/12; 568/312; 568/317 |
| Intern'l Class: |
C07C 255/07; C07C 303/16; C07C 045/37 |
| Field of Search: |
558/371
560/12,82
568/312,317
|
References Cited
Other References
Ozawa, fumuyuki et al., Palladium-Catalyzed Double Carbonylation of Aryl
Halides Affording alpha-keto Amides. (1986), 51, pp415-417.
|
Primary Examiner: McKane; Joseph
Assistant Examiner: Sackey; Ebenezer
Attorney, Agent or Firm: Wiggin & Dana
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application No.
60/097,472 filed Aug. 21, 1998.
Claims
What is claimed is:
1. A process for preparing an alpha-arylated or -vinylated carbonyl
compounds, comprising the step of:
reacting a compound having at least one carbonyl group and an atom alpha to
said carbonyl group bearing at least one hydrogen atom with an arylating
or vinylating compound selected from the group consisting of ketone,
amides, esters, carboxylic acids, thioesters, amidines, anhydrides,
.beta.-dicarbonyl compounds, .alpha.-dicarbonyl compounds, malononitriles,
compounds with carbonyl groups .beta.- to sulfoxides, sulfones,
phosphates, phosphate esters, and nitriles in the presence of a base and a
transition metal catalyst under reaction conditions effective to form said
alpha-arylated or vinylated carbonyl compound, said transition metal
catalyst having the formula:
X.sub.n M(ER.sub.1-4).sub.m
wherein X is an optional ligand, M is a group 8 transition metal, E is an
element bearing a nonbonding electron pair when E is not bonded to the
metal, and R is a substituent bonded to E through a carbon, nitrogen,
oxygen, or sulfur atom, with the proviso that R.sub.3 cannot contain 3
aryl groups, n is an integer from 0 to 4, and m is an integer from 1-4.
2. The process of claim 1, wherein said compound having at least one
carbonyl group and an atom alpha to said carbonyl group bearing at least
one hydrogen atom is selected from those having the structure
##STR48##
where R and R' are independently selected from the group consisting of
hydrogen, alkyl, aryl or heteroaryl, alkoxo, vinyl, alkyl, and amido; and
R" is selected from the group consisting of hydrogen, aryl or heteroaryl,
alkoxo, vinyl, alkyl, and amido.
3. The process of claim 1, wherein said compound having at least one
carbonyl group and an atom alpha to said carbonyl group bearing at least
one hydrogen atom is selected from the group consisting of acetophenone,
propiophenone, isobutyrophenone, acetone, and diethyl ketone.
4. The process of claim 1, wherein said arylating compound is selected from
the group consisting of 5, 6, or 7-membered aryl ring structures
comprising an activated group.
5. The process of claim 4, wherein said arylating compound is selected from
those having the structure
##STR49##
wherein X is a halogen atom or a sulfur-containing leaving group, and
R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are selected from the
group consisting of H; CN; alkyl, vinyl, alkenyl, formyl; CF.sub.3 ;
CCl.sub.3 ; halide, C.sub.6 H.sub.5, amide, C(O)N(CH.sub.3).sub.2,
C(O)N(CH.sub.2 CH.sub.3).sub.2, C(O)N(CH.sub.2 CH.sub.2 CH.sub.3).sub.2,
acyl, C(O)--C.sub.6 H.sub.5, ester, aryl, alkoxy, thioalkoxy, phosphino,
amino, and heterocyclic.
6. The process of claim 4, wherein said arylating compound is selected from
those having the structure
##STR50##
wherein X is Br or Cl, and R is p-CN, m-CN, p-t-Bu, m-OMe, p-OMe o-Me,
p-C(O)H, p-CF.sub.3, p-Ph, p-C(O)Et.sub.2, p-H, and p-C(O)Ph.
7. The process of claim 1, wherein said vinylating compound is selected
from the group consisting of vinyl halides, vinyl sulfonates, vinyl
tosylates, and vinyl phosphates.
8. The process of claim 1, wherein said base is selected from the group
consisting of alkali metal hydroxides, alkali metal alkoxides, metal
carbonates, alkali metal amides, alkali metal aryl oxides, tertiary
amines, tetraalkylammonium hydroxides, diaza organic bases, and silyl
bases.
9. The process of claim 1, wherein said Group 8 metal is selected from the
group consisting of palladium, platinum, and nickel.
10. The process of claim 1, wherein said optional ligand is selected from
the group consisting of halide, acetate, and alkene.
11. The process of claim 1, wherein L is an atom selected from Group 14,
15, or 16 of the Periodic Table.
12. The process of claim 11, wherein L is phosphorous.
13. The method of claim 1, wherein R is a substituent selected from the
group consisting of alkyl, cycloalkyl, aryl, alkoxo, amido, cyclic, and
heterocyclic.
14. The method of claim 1, wherein said R is selected from the group
consisting of t-butyl, N(CH.sub.2 CH.sub.3).sub.2, cyclohexyl, cyclohexyl,
dialkylamino, o-tolyl, o-anisyl, phenyl, 2-biphenylyl, ferrocenyl, and
substituted ferrocenyl.
15. The process of claim 1, wherein said catalyst is prepared in situ in
the reaction mixture.
16. The process of claim 15, wherein the catalyst is prepared from an
alkene or diene complex of a Group 8 transition metal complex or a Group 8
transition metal carboxylate.
17. The process of claim 1, wherein the alkene complex of the Group 8
transition metal is di(benzylidene)acetone.
18. The process of claim 1, wherein the catalyst is anchored or supported
on a catalyst support.
19. The process of claim 1, wherein said reaction conditions further
comprise a solvent selected from the group consisting of aromatic
hydrocarbons, chlorinated aromatic hydrocarbons, ethers, water, and
aliphatic alcohols.
20. The process of claim 1, further comprising the step of isolating said
alpha-arylated carbonyl compound.
21. The process of claim 1, wherein said transition metal catalyst is a
non-racemic chiral catalyst and generates a non-racemic product having
optical activity.
Description
FIELD OF THE INVENTION
This invention relates to a general process for alpha-arylation or
vinylation of carbonyl-containing compounds, and more particularly to a
general process for synthesizing alpha-arylated or -vinylated
carbonyl-containing compounds from arylating or vinylating compounds and
carbonyl containing compounds using a transition metal catalyst.
DESCRIPTION OF THE RELATED ART
The palladium-catalyzed coupling to form C--C bonds between aryl and vinyl
halides or triflates and a carbon nucleophile is one of the most widely
used transition metal-catalyzed reactions. (Stille, J. K. Angew. Chem.,
Int. Ed. Engl., 25:508-524 (1986); Miyaura, N. et al., Chem. Rev.,
95:2457-2483 (1995); Negishi, E. Acc. Chem. Res., 15:340-348 (1982)). The
related cross-coupling reactions involving ketone enolates as the
nucleophile are also very important commercially. However, this class of
cross-coupling reaction has been limited to tin enolates, silyl-enol
ethers in combination with tin fluoride, intramolecular examples, or
examples with acid ketones and metal ion catalysts in low yields (Kosugi,
M. et al., Bull. Chem. Soc. Jpn., 57:242-246 (1984)).
Many transition metal-catalyzed approaches to ketone arylation using
pre-formed main group enol ethers (Carfagna, C. et al., J. Org. Chem.,
56:261-263 (1991); Durandetti, M. et al., J. Org. Chem. 61:1748-1755
(1996); Fauvargue, J. F. et al., J. Organomet. Chem., 177:273-281 (1979))
or bismuth or lead reagents (Barton, D. H. R. et al., Tet. Letters,
27:3619-3522 (1986); Barton, D. H. R. et al., J. Chem. Soc., Perkin Trans.
1:1365-1375 (1992)) have been investigated. However, use of toxic
main-group reagents, low product yields, and multi-step preparation of
compounds make these procedures particularly difficult to exploit
commercially. In addition, arylation using a metal halide in the absence
of a chelating ligand has been shown (Satoh et al., Angew. Chem. Int. Ed.
Engl. 36:1740-1741 (1997)); however, the yield of product is unacceptably
low for commercial purposes.
It would be advantageous to prepare alpha-aryl carbonyl-containing
compounds from arylating compounds such as aryl halides and/or aryl
sulfonates because aryl halides are generally inexpensive and readily
available, while aryl sulfonates are easily prepared from phenols.
U.S. patent application Ser. No. 09/173,527 discloses a transition metal
catalyzed process for preparing arylated carbonyl-containing compounds.
However, this process uses chelating ligands as part of the catalyst, and
such chelating ligand catalysts may not be useful in many synthetic
preparations.
In view of the above, a need exists for a general and efficient process of
synthesizing alpha-aryl carbonyl-containing compounds. The discovery and
implementation of such a process would simplify the preparation of
commercially significant organic alpha-aryl carbonyl-containing compounds
and would enhance the development of novel pharmacologically active
compounds. The present invention is believed to be an answer to that need.
SUMMARY OF THE INVENTION
In one aspect, the present invention is directed to a process for preparing
alpha-arylated or -vinylated carbonyl-containing compounds, comprising the
step of reacting a compound having at least one carbonyl group with an
arylating or vinylating compound in the presence of a base and a
transition metal catalyst under reaction conditions effective to form the
alpha-arylated or -vinylated carbonyl-containing compound, the transition
metal catalyst having the formula X.sub.n M(ER.sub.1-4).sub.m, wherein X
is an optional ligand, M is a group 8 transition metal, E is an element
bearing a nonbonding electron pair when E is not bonded to the metal, and
R is a substituent bonded to E through a carbon, nitrogen, oxygen, or
sulfur atom, with the proviso that R.sub.3 cannot contain 3 aryl groups, n
is an integer from 0 to 4, and m is an integer from 1-4.
These and other aspects will become apparent upon reading the following
detailed description of the invention.
DETAILED DESCRIPTION OF THE INVENTION
It now has been surprisingly found, in accordance with the present
invention, that a solution is provided to the problem of providing a
general and efficient process of synthesizing alpha-arylated or -vinylated
carbonyl-containing compounds from a starting material having at least one
carbonyl group, and an arylating or vinylating compound. The present
inventors have solved this problem by utilizing reaction conditions that
include a base and a transition metal catalyst having the formula
X.sub.n M(ER.sub.1-4).sub.m
wherein X is an optional ligand, M is a group 8 transition metal, E is an
element bearing a nonbonding electron pair when E is not bonded to the
metal, and R is a substituent bonded to E through a carbon, nitrogen,
oxygen, or sulfur atom, with the proviso that R.sub.3 cannot contain 3
aryl groups, n is an integer from 0 to 4, and m is an integer from 1-4.
The process of the present invention provides a general process for
production of alpha-arylated carbonyl-containing compounds, a class of
compound which is particularly significant in the development of
pharmacologically active compounds and production of polymers and
oligomers.
As defined herein, "alpha-carbon" refers to the carbon atom directly
adjacent to a carbonyl (C.dbd.O) group in an organic molecule. The phrases
"alpha arylation", "alpha arylating", and "alpha arylated" refer to
attachment of an aryl group onto the alpha carbon of an organic compound.
Similarly, the phrases "alpha vinylation", "alpha vinylating", and "alpha
vinylated" refer to attachment of a vinyl group onto the alpha carbon of
an organic compound. The terms "aryl" and "aryl group" are defined as a
compound or compounds whose molecules have the ring structure
characteristic of benzene, naphthalene, phenanthroline, anthracene,
pyridine, furan, indole, and the like. The term "vinyl" and "vinyl group"
are defined herein as a group containing a C--C double bond, that includes
the carbon attached to an alpha carbon. The phrase "nonbonding electron
pair" refers to a pair of electrons on an atom that do not participate in
covalent bond formation.
The process of the present invention is directed to the synthesis of
alpha-arylated and -vinylated carbonyl-containing compounds, particularly
alpha-arylated ketones and malonates. The process of the invention
comprises reacting a compound having at least one carbonyl (C=O) group
with an arylating or vinylating compound in the presence of a base and a
transition metal catalyst under reaction conditions effective to form an
alpha-arylated or -vinylated carbonyl-containing compound. The transition
metal catalyst has the formula
X.sub.n M(ER.sub.1-4).sub.m
wherein X is an optional ligand, M is a group 8 transition metal, E is an
element bearing a nonbonding electron pair when E is not bonded to the
metal, and R is a substituent bonded to E through a carbon, nitrogen,
oxygen, or sulfur atom, with the proviso that R.sub.3 cannot contain 3
aryl groups, n is an integer from 0 to 4, and m is an integer from 1-4.
More specifically, the process of this invention can be represented by
Scheme I:
##STR1##
Briefly, in Scheme I, an arylating (Ar-X) or vinylating (vinyl-X) compound
is reacted with a carbonyl-containing compound in the presence of a base,
a chelating ligand (ER.sub.1-4), and a Group 8 metal (M) to form an
alpha-arylated carbonyl-containing compound. This reaction and each of the
components are described in more detail below.
The arylating compound used in the process of the present invention may be
any 5, 6, or 7-membered aryl ring structure, including heterocyclic ring
structures, that include an activated group, such as a leaving group. In
one embodiment, the arylating compound has the structure of formula (II):
##STR2##
In formula (II), X may be any halide atom (F, Cl, Br, I), or any
sulfur-containing leaving group (e.g., triflate, sulfonate, tosylate,
oxygen, and the like) known in the art. Bromides and chlorides are
especially preferred in the process of the present invention. R.sub.1,
R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are independently selected from H;
CN; alkyl, such as methyl, ethyl, propyl, n-butyl, t-butyl, and the like;
formyl; CF.sub.3 ; CCl.sub.3 ; C.sub.6 H.sub.5 ; amide such as
C(O)N(CH.sub.3).sub.2, C(O)N(CH.sub.2 CH.sub.3).sub.2, C(O)N(CH.sub.2
CH.sub.2 CH.sub.3).sub.2, and the like; acyl, such as C(O)--C.sub.6
H.sub.5, and the like; ester, aryl, alkoxy, amino, thioalkoxy, phosphino,
vinyl, halide, and the like. In an alternative embodiment, one or more of
R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 may be joined to form a
heterocyclic structure.
Arylating and vinylating compounds that are also useful in the method of
the invention include any molecule such as that shown in formuala (II)
that contains an activated aryl or vinyl group. As used herein, the term
"activated" refers to conventional leaving groups at position X such as
halide atoms (F, Cl, Br, I), any oxygen-containing leaving group such as a
sulfonate (triflate, tosylate, and the like), phosphate or phosphate
esters, actates, any other leaving group X whose conjugate acid HX has a
pK.sub.a less than 16, or other leaving groups known in the art.
Exemplary activated aryl and vinyl groups useful in the present invention
include substituted or unsubstituted aryl halides (e.g., bromobenzene or
chlorobenzene), vinyl halides, substituted or unsubstituted aryl
sulfonates, vinyl sulfonates, vinyl tosylates, vinyl phosphates, and the
like.
Preferred arylating compounds used in the process of the invention include
aryl halides such as bromobenzene, 4-bromo-benzonitrile, 4-bromo-t-butyl
benzene, 3-bromo-methoxy benzene, 2-bromo toluene, para-formyl phenyl
bromide, p-CF.sub.3 phenyl bromide, p-phenyl phenyl bromide,
p-C(O)N(CH.sub.2 CH.sub.3).sub.2 phenyl bromide, and p-C(O)-C.sub.6
H.sub.5 phenyl bromide.
According to the process of the invention, compounds containing at least
one carbonyl group include any carbonyl-containing compound that possesses
an alpha-carbon. The structure of a preferred set of carbonyl-containing
compounds is
##STR3##
where R and R' are independently selected from hydrogen, alkyl, aryl or
heteroaryl, alkoxo, vinyl, alkyl, or amido; and R" is hydrogen, aryl or
heteroaryl, alkoxo, vinyl, alkyl, or amido. Preferred aryl and heteroaryl
groups for R" include phenyl, pyrrole, N-substituted pyrrole, furan,
thiophene, and the like.
Exemplary carbonyl-containing groups include ketones, amides, esters,
carboxylic acids, thioesters, amidines, anhydrides; .beta.-dicarbonyl
compounds such as malonates, acetoacetates, .beta.-diketones, and the
like; and .alpha.-dicarbonyl compounds, such as .alpha.-diketones,
.alpha.-ketoesters, .alpha.-ketamides, and the like. Additional useful
compounds include malononitriles, compounds with carbonyl groups .beta.-
to sulfoxides, sulfones, phosphates, phosphate esters, and nitrites.
Particularly useful carbonyl-containing compounds include alkyl aryl
ketones, such as acetophenone, propiophenone, isobutyrophenone, and
dialkyl ketones, such as acetone and diethyl ketone.
The base shown in Scheme I is required for the process of the present
invention. Any base may be used so long as the process of the invention
proceeds to the alpha-aryl product. It may be important in this regard
that the base does not displace all of the chelating ligands on the
catalyst. Nuclear magnetic resonance, infrared, and Raman spectroscopies,
for example, are useful in determining whether the ligands remain bonded
to the Group 8 metal or whether the ligands have been displaced by the
base.
Non-limiting examples of suitable bases include alkali metal hydroxides,
such as sodium and potassium hydroxides; alkali metal alkoxides, such as
sodium t-butoxide; metal carbonates, such as potassium carbonate, cesium
carbonate, and magnesium carbonate; alkali metal aryl oxides, such as
potassium phenoxide; alkali metal amides, such as lithium amide or lithium
diisopropylamide; tertiary amines, such as triethylamine and
tributylamine; (hydrocarbyl)ammonium hydroxides, such as
benzyltrimethyl-ammonium hydroxide and tetraethylammonium hydroxide; diaza
organic bases, such as 1,8-diazabicyclo[5.4.0]-undec-7-ene and
1,8-diazabicyclo-[2.2.2.]-octane, and silyl compounds such as potassium
hexamethyldisilazide (KN(Si(CH.sub.3).sub.3).sub.2). Preferably, the base
is an alkali alkoxide or a silyl-containing compound.
The quantity of base which is used can be any quantity which allows for the
formation of the alpha-aryl product. Preferably, the molar ratio of base
to arylating compound ranges from about 1:1 to about 3:1, and more
preferably between about 1:1 and 2:1.
The catalyst, designated X.sub.n M(ER.sub.1-4).sub.m in Scheme I, is
characterized as comprising a Group 8 transition metal atom or ion (M), a
ligand containing an element bearing a nonbinding electron pair (E) when E
is not bonded to the metal, and one to four substituents R that are bonded
to E through a carbon, nitrogen, oxygen, or sulfur atom. In the catalyst,
three aryl groups cannot be used for R, n is an integer from 0 to 4, and m
is an integer from 1-4. The catalyst also contains a chiral center and
results in a non-racemic chiral catalyst that is capable of generating
non-racemic products as shown in more detail in Examples 32-34.
The Group 8 transition metal atom or ion is preferably selected from iron,
cobalt, nickel, ruthenium, rhodium, palladium, osmium, iridium, and
platinum. More preferably, the Group 8 metal is palladium, platinum, or
nickel, and most preferably, palladium. The Group 8 metal may exist in any
oxidation state ranging from the zero-valent state to any higher variance
available to the metal.
As indicated above, E is an element that contains a nonbonding electron
pair when E is not bonded to the metal. Preferred elements for E in the
transition metal catalyst include elements from Group 14 , Group 15, and
Group 16 of the Periodic Table (formerly known as Group IVB, Group VB, and
Group VIB, respectively). Preferred elements for E include phosphorus,
nitrogen, arsenic, and carbon in the form of a carbene. A particularly
preferred element for E is phosphorous.
As indicated above, the R substituents in the catalyst may be any
substituent that is bonded to E through a carbon, nitrogen, oxygen or
sulfur atom. However, the catalyst of the invention may not have 3 aryl
groups. Exemplary groups include t-butyl, cyclohexyl, dialkylamino,
o-tolyl, o-anisyl, phenyl, 2-biphenylyl, ferrocenyl and substituted
ferrocenyl groups.
Particular catalysts useful in the method of the invention include a
combination of bis-(dibenzylideneacetone)palladium, palladium acetate, or
palladium dihalides and the ligand ER.sub.1-4.
Methods for preparing the aforementioned catalysts are known to those
skilled in the art. For a description of general synthetic techniques, see
Inorganic Synthesis: Reagents for Transition Metal Complex and
Organometallic Systems; R. J. Angelici, Ed., Wiley-Interscience: New York,
1990, Vol. 28, pp. 77-135 (Chapter 2), incorporated herein by reference,
wherein representative preparations of Group 8 complexes containing amine,
phosphine, and arsine ligands are taught.
As an alternative embodiment of this invention, the catalyst may be
anchored or supported on a support. Useful supports include refractory
oxide, such as silica, alumina, titania, or magnesia; charcoal; or an
aluminosilicate clay, or molecular sieve or zeolite; or an organic
polymeric resin.
The transition metal catalyst may be synthesized first and thereafter
employed in the arylation process. Alternatively, the catalyst can be
prepared in situ in the arylation reaction mixture. If the latter mixture
is employed, then a Group 8 catalyst precursor compound and the desired
chelating ligand are independently added to the reaction mixture wherein
formation of the transition metal catalyst occurs in situ. Suitable
precursor compounds include alkene and diene complexes of the Group 8
metals, preferably, (dibenzylidene)acetone (dba) complexes of the Group 8
metals, as well as, monodentate phosphine complexes of the Group 8 metals,
and Group 8 carboxylates. In the presence of the ligand complex, in situ
formation of the transition metal catalyst occurs. Non-limiting examples
of suitable precursor compounds include
[bis-(dibenzylidene)acetone]palladium (0),
tetrakis-(triphenylphosphine)-palladium (0),
tris-[(dibenzylidene)acetone]palladium (0), tris-[(dibenzylidene)
acetone]-dipalladium (0), palladium acetate, and the analogous complexes
of iron, cobalt, nickel, ruthenium, rhodium, osmium, iridium, and
platinum. Any of the aforementioned catalyst precursors may include a
solvent of crystallization. Group 8 metals supported on carbon,
preferably, palladium or nickel on carbon, can also be suitably employed
as a precursor compound. Preferably, the catalyst precursor compound is
bis-[(dibenzylidene)acetone]palladium(0).
The quantity of transition metal catalyst which is employed in the process
of this invention is any quantity which promotes the formation of the
alpha-aryl product. Generally, the quantity is a catalytic amount, which
means that the catalyst is used in an amount which is less than
stoichiometric relative to the unsaturated organic sulfonate. Typically,
the transition metal catalyst ranges from about 0.01 to about 20 mole
percent, based on the number of moles of the carbonyl-containing compound
used in the reaction. Preferably, the quantity of transition metal
catalyst ranges from about 1 to about 10 mole percent, and more preferably
from about 3 to about 8 mole percent, based on the moles of the
carbonyl-containing compound.
The process described herein may be conducted in any conventional reactor
designed for catalytic processes. Continuous, semi-continuous, and batch
reactors can be employed. If the catalyst is substantially dissolved in
the reaction mixture as in homogeneous processes, then batch reactors,
including stirred tank and pressurized autoclaves, can be employed. If the
catalyst is anchored to a support and is substantially in a heterogeneous
phase, then fixed-bed and fluidized bed reactors can be used. In the
typical practice of this invention the carbonyl-containing compound,
arylating compound, base, and catalyst are mixed in batch, optionally with
a solvent, and the resulting mixture is maintained at a temperature and
pressure sufficient to prepare the alpha-arylated product.
Any solvent can be used in the process of the invention provided that it
does not interfere with the formation of the alpha-aryl product. Both
aprotic and protic solvents are acceptable. Suitable aprotic solvents
include, but are not limited to, aromatic hydrocarbons, such as toluene
and xylene, chlorinated aromatic hydrocarbons, such as dichlorobenzene;
and ethers, such as tetrahydrofuran. Suitable protic solvents include, but
are not limited to, water and aliphatic alcohols, such as ethanol,
isopropanal, and cyclohexonal, as well as glycols and other polyols. The
amount of solvent which is employed may be any amount, preferably an
amount sufficient to solubilize, at least in part, the reactants and base.
A suitable quantity of solvent typically ranges from about 1 to about 100
grams solvent per gram reactants. Other quantities of solvent may also be
suitable, as determined by the specific process conditions and by the
skilled artisan.
Generally, the reagents may be mixed together or added to a solvent in any
order. If it is desirable or necessary to remove air, the solvent and
reaction mixture can be sparged with a non-reactive gas, such as nitrogen,
helium, or argon. The process conditions can be any operable conditions
which yield the desired alpha-aryl product. Beneficially, the reaction
conditions for this process are mild. For example, a preferred temperature
for the process of the present invention ranges from about ambient, taken
as about 22.degree. C., to about 150.degree. C., and preferably, from
about 80.degree. C. to about 110.degree. C. The process may be run at
subatmospheric pressures if necessary, but typically proceeds sufficiently
well at about atmospheric pressure. The process is generally run for a
time sufficient to convert as much of the carbonyl-containing compound to
product as possible. Typical reaction times range from about 30 minutes to
about 24 hours, but longer times may be used if necessary.
The product can be recovered by conventional methods known to those skilled
in the art, including, for example, distillation, crystallization,
sublimation, and gel chromatography. The yield of product will vary
depending upon the specific catalyst, reagents, and process conditions
used. For the purposes of this invention, "yield" is defined as the mole
percentage of alpha-aryl product recovered, based on the number of moles
of carbonyl-containing compound employed. Typically, the yield of
alpha-aryl product is greater than about 25 mole percent. Preferably, the
yield of alpha-aryl product is greater than about 60 mole percent, and
more preferably, greater than about 80 mole percent.
The following examples are intended to illustrate, but in no way limit the
scope of the present invention. All parts and percentages are by weight
and all temperatures are in degrees Celsius unless explicitly stated
otherwise.
EXAMPLES 1-14
Examples 1-14 illustrate reactions of several ketones and malonates with
various arylating compounds.
Reactions using tri-t-butylphosphine as ligand: The reaction conditions and
results are shown in Table I. A typical procedure is given for the
reaction in entry 3.
1,2-Diphenyl-1-ethanone: Pd(OAc).sub.2 (2.3 mg, 0.010 mmol),
tri-t-butylphosphine (2.1 mg, 0.010 mmol) and NaO.sup.t Bu (211 mg, 2.20
mmol) were suspended in 1 mL of THF in a screw-capped vial. The vial was
sealed with a cap containing a PTFE septum and removed from the dry box.
Bromobenzene (157 mg, 1.00 mmol) and acetophenone (132 mg, 1.10 mmol) were
added to the reaction mixture by syringe. The reaction mixture was stirred
at 25.degree. C. and monitored by GC analysis. The crude reaction was
diluted with ether and washed with 1N HCl, water and brine. The organic
layer was dried over Na.sub.2 SO.sub.4, filtered and concentrated in
vacuo. The residue was chromatographed on silica gel (hexane/EtOAc=95/5)
to give 188 mg (96%) of 1,2-Diphenyl-1-ethanone: .sup.1 H NMR:
(CDCl.sub.3) .delta. 8.02 (d, J=7.1 Hz, 2H), 7.58-7.26 (m, 8H), 4.31 (s,
2H); .sup.13 C{.sup.1 H} NMR: (CDCl.sub.3) .delta. 197.52, 136.79, 134.67,
133.09, 129.54, 129.50, 128.64, 128.62, 126.88, 45.50.
2-(4-Benzoylphenyl)-1-phenyl-1-propanone: Pd(OAc).sub.2 (4.5 mg, 0.020
mmol), Tri-t-butylphosphine (4.1 mg, 0.020 mmol), NaO.sup.t Bu (144 mg,
1.50 mmol), 4-Bromobenzophenone (261 mg, 1.00 mmol) and Propiophenone (148
mg, 1.10 mmol) were used. Reaction at 70.degree. C. for 12 h gave 304 mg
(97%) of 2-(4-Benzoylphenyl)-1-phenyl-1-propanone after silica gel
chromatography (hexane/EtOAc=85/15). .sup.1 H NMR: (CDCl.sub.3) .delta.
7.96 (d, J=7.7 Hz, 2H) , 7.76-7.75 (m, 4H), 7.58 (t, J=7.2 Hz, 1H), 7.52
(t, J=7.1 Hz, 1H), 7.47 (t, J=7.7 Hz, 2H), 7.43-7.40 (m, 4H), 4.79 (q,
J=6.9 Hz, 1H), 1.59 (d, J=6.9 Hz, 3H); .sup.13 C{.sup.1 H} NMR:
(CDCl.sub.3) .delta. 199.66, 196.14, 146.16, 137.51, 136.23, 133.10,
132.40, 130.82, 129.94, 129.80, 128.75, 128.63, 128.26, 127.79, 47.72,
19.37. MS m/e (relative intensity): 314 (10), 105 (100), 77 (38), 51 (13).
Anal. Calcd for C.sub.22 H.sub.18 O.sub.2 : C, 84.05; H, 5.77. Found: C,
83.91: H, 5.88.
Reaction using 0.005 mol % catalyst: Pd(OAc).sub.2 (0.5 mg, 0.0023 mmol),
tri-t-butylphosphine (0.4 mg, 0.0020 mmol) and NaO.sup.t Bu (5.80 g, 60.3
mmol) were suspended in 5 mL of THF in a screw-capped test tube.
Bromobenzene (6.28 g, 40.0 mmol) and propiophenone (5.90 g, 44.0 mmol)
were added to the reaction mixture in the drybox. The reaction tube was
sealed with a cap and the mixture was stirred for 24 h at 60.degree. C.
The reaction was diluted with ether and washed with water and brine. The
organic layer was dried over Na.sub.2 SO.sub.4, filtered and concentrated
in vacuo. The residue was chromatographed on silica gel
(hexane/EtOAc=95/5) to give 8.2 g (98%) of 1,2-Diphenyl-1-propanone.
Reaction of propiophenone with p-tolyltosylate: Pd(OAc).sub.2 (9.0 mg,
0.040 mmol), ligand (27.1 mg, 0.050 mmol), NaO.sup.t Bu (144 mg, 1.50
mmol) and 4-methylphenyl-p-toluene sulfonate (262 mg, 1.00 mmol) were
suspended in 1 mL of dioxane in a screw-capped vial. The vial was sealed
with a cap containing a PTFE septum and removed from the dry box.
Propiophenone (132 mg, 1.10 mmol) was added to the reaction mixture by
syringe. The reaction mixture was stirred at 100.degree. C. and monitored
by GC analysis. The crude reaction was diluted with ether and washed with
1N HCl, water and brine. The organic layer was dried over Na.sub.2
SO.sub.4, filtered and concentrated in vacuo. The residue was
chromatographed on silica gel (hexane/EtOAc=95/5) to give 135 mg (60%) of
2-(4-Methoxyphenyl)-1-phenyl-1-propanone.
Reactions using tri-cyclohexylphosphine as ligand: The reaction conditions
and results are shown in Table I. A typical procedure is given for the
reaction in Example 8.
1,2-Diphenyl-1-propanone: Pd(OAc).sub.2 (4.5 mg, 0.020 mmol),
Tri-cyclohexyphosphine (5.6 mg, 0.020 mmol) and NaO.sup.t Bu (144 mg, 1.50
mmol) were suspended in 1 mL of THF in a screw-capped vial. The vial was
sealed with a cap containing a PTFE septum and removed from the dry box.
Chlorobenzene (113 mg, 1.00 mmol) and propiophenone (144 mg, 1.10 mmol)
were added to the reaction mixture by syringe. The reaction mixture was
stirred at 50.degree. C. and monitored by GC analysis. The crude reaction
was diluted with ether and washed with water and brine. The organic layer
was dried over Na.sub.2 SO.sub.4, filtered and concentrated in vacuo. The
residue was chromatographed on silica gel (hexane/EtOAc=95/5) to give 204
mg (97%) of 1,2-Diphenyl-1-propanone.
Reaction of Malonates with aryl halides: Phenyl di-tert-butylmalonate:
Pd(OAc).sub.2 (9.0 mg, 0.040 mmol), D.sup.t BPF (23.8 mg, 0.050 mmol) and
NaO.sup.t Bu (288 mg, 3.00 mmol) were suspended in 2 mL of dioxane in a
screw-capped vial. The vial was sealed with a cap containing a PTFE septum
and removed from the dry box. Chlorobenzene (225 mg, 2.00 mmol) and
di-tert-butyl malonate (480 mg, 2.20 mmol) were added to the reaction
mixture by a syringe. The reaction was heated at 100.degree. C. and
monitored by GC analysis. The reaction mixture was diluted with ether and
was washed with water and brine. The organic layer was dried over Na.sub.2
SO.sub.4, filtered and concentrated in vacuo. The residue was
chromatographed on silica gel (hexane/EtOAc=80/20) to give 465 mg (80%) of
phenyl di-tert-butylmalonate: .sup.1 H NMR: (CDCl.sub.3) .delta. 7.40-7.33
(m, 5H), 4.44 (s, 1H), 1.47 (s, 18H); .sup.13 C{.sup.1 H} NMR:
(CDCl.sub.3) .delta. 167.44, 133.51, 129.30, 128.38, 127.83, 81.92, 60.10,
27.87.
Phenyl diethylmalonate: Pd(OAc).sub.2 (4.5 mg, 0.020 mmol), P(.sup.t
Bu).sub.3 (4.1 mg, 0.020 mmol) and NaO.sup.t Bu (100 mg, 1.04 mmol) were
suspended in 2 mL of dioxane in a screw-capped vial. The vial was sealed
with a cap containing a PTFE septum and removed from the dry box.
Bromobenzene (157 mg, 1.00 mmol) and diethyl malonate (176 mg, 1.10 mmol)
were added to the reaction mixture by syringe. The reaction was heated at
70.degree. C. and monitored by GC analysis. The reaction mixture was
diluted with ether and was washed with water and brine. The organic layer
was dried over Na.sub.2 SO.sub.4, filtered and concentrated in vacuo. The
residue was chromatographed on silica gel (hexane/EtOAc=80/20) to give 205
mg (86%) of phenyl diethylbutylmalonate: .sup.1 H NMR: (CDCl.sub.3)
.delta. 7.42-7.33 (m, 5H), 4.62 (s, 1H), 4.23 (q, J=7.3 Hz, 4H), 1.27 (t,
J=7.3 Hz, 6H); .sup.13 C{.sup.1 H} NMR: (CDCl.sub.3) .delta. 168.13,
132.84, 129.25, 128.56, 128.16, 61.75, 57.98, 13.98.
The results of the above experiments are summarized in I.
TABLE I
__________________________________________________________________________
Reaction of Ketones and Malonates
Ketone/ mol % Pd,
Entry
ArX Malonate Product Ligand Conditions
Yield
__________________________________________________________________________
1 PhBr
##STR4##
##STR5## 0.5% Pd(dba).sub.2, P(t-Bu).sub.3
25.degree. C., 2
97%
2 PhBr
##STR6##
##STR7## 0.00% Pd(dba).sub.2, P(t-Bu).sub.3
60.degree. C., <24
96%
3 PhBr
##STR8##
##STR9## 1% Pd(OAc).sub.2 P(t-Bu).sub.3
25.degree. C., 6
96%
4 PhBr
##STR10##
##STR11## 1% Pd(OAc).sub.2 P(t-Bu).sub.3
50.degree. C., 12
92%
5 3-Me-- OC.sub.6 H.sub.4 Br
##STR12##
##STR13## 1% Pd(OAc).sub.2 P(t-Bu).sub.3
50.degree. C., 12
83%
6 PhBr
##STR14##
##STR15## 1% Pd(OAc).sub.2 P(t-Bu).sub.3
50.degree. C., 3
73%
7 PhCl
##STR16##
##STR17## 2% Pd(OAc).sub.2 P(t-Bu).sub.3
70.degree. C., 4
90%
8 PhCl
##STR18##
##STR19## 2% Pd(OAc).sub.2 P(Cy).sub.3
50.degree. C., 12
93
9 3-Me-- OC.sub.6 H.sub.4 Cl
##STR20##
##STR21## 2% Pd(OAc).sub.2 P(t-Bu).sub.3
70.degree. C., 12
69%
10 4-Me-- OC.sub.6 H.sub.3 Cl
##STR22##
##STR23## 2% Pd(OAc).sub.2 P(t-Bu).sub.3
70.degree. C., 12
91%
11 4-Me-- OC.sub.6 H.sub.4 Cl
##STR24##
##STR25## 2% Pd(OAc).sub.2 P(Cy).sub.3
70.degree. C., 12
93%
12 3-Me-- OC.sub.6 H.sub.4 Cl
##STR26##
##STR27## 2% Pd(OAc).sub.2 P(t-Bu).sub.3
70.degree. C., 12
82%
13 4-Ph--C(O)-- C.sub.6 H.sub.4 Cl
##STR28##
##STR29## 2% Pd(OAc).sub.2 P(t-Bu).sub.3
70.degree. C., 24
95%
14 PhBr
##STR30##
##STR31## 2% Pd(OAc).sub.2 P(t-Bu).sub.3
70.degree. C., 3
80%
__________________________________________________________________________
EXAMPLES 15-21
Table II shows results for a variety of conditions for the following
reaction:
##STR32##
The catalyst, metal source, conditions, and yields are in Table II.
TABLE II
__________________________________________________________________________
Yield
Example
Metal Ligand Conditions
(PhPr:Product)
__________________________________________________________________________
15 2% Pd(dba).sub.2
##STR33## RT 50:50
16 5% Pd(dba).sub.2
4% tBuP(NEt.sub.2).sub.2
RT 11:89
17 2% Pd(dba).sub.2
2% P(NEt.sub.2).sub.2
RT No Reaction
100.degree. C. 6h
0:100
18 2% Pd(dba).sub.2
1.5% P(Net.sub.2).sub.3
50.degree. C.
0:100
19 2% Pd(dba).sub.2
4% P(Net.sub.2).sub.3
50.degree. C.
19:81
20 2% Pd(dba).sub.2
1.5% P(NMe.sub.2).sub.3
RT 64:36
21 2% Pd(dba).sub.2
##STR34## RT 36:64
__________________________________________________________________________
These reactions demonstrate that the ligand need not contain R groups
bonded to E by carbon, but can include ligands with R groups bonded to E
by nitrogen and oxygen and combinations of those bonded by C, N, and O are
effective ligands for these reactions.
EXAMPLES 22-31
Examples 22-31 show results of the following chemical reaction under
various conditions and with various catalysts.
##STR35##
TABLE III
__________________________________________________________________________
Example
ArX Pd(dba).sub.2
Ligand Temp.
ArX = Product
__________________________________________________________________________
22 PhCl 5 mol %
4 mol % 100.degree. C.
0:100
tBuP(NEt.sub.2).sub.2
23
2 mol %
##STR36## 70.degree. C., 100.degree. C., 24
h No Reaction 9:91
24
##STR37##
2 mol %
##STR38## 70.degree. C., 100.degree. C., 24
h No Reaction No Product
25 PhBr 5 mol %
##STR39## RT 3:97
26
##STR40##
5 mol %
4 mol % tBu(NEt.sub.2).sub.3
100.degree. C.
0:100
27 PhBr 5 mol %
4 mol % RT 15:85
(iPr.sub.2)PNEt.sub.2
28 PhBr 5 mol %
4 mol % RT 6:94
(tBu.sub.2)PNEt.sub.2
29 PhBr 5 mol %
4 mol % RT 29:71
Ph--P(NEt.sub.2).sub.2
30 PhBr 5 mol %
4 mol % RT 55:45
2,8,9-
Trimethyl-1-
phospha-
2,5,8,9-
tetraazabicyclo
[3.3.3]undecane
31 PhBr 5 mol %
##STR41## RT 20:80
__________________________________________________________________________
These results demonstrate that catalyts containing the ligands with R
groups bonded to E through oxygen and nitrogen are capable of reacting
with aryl chlorides as well as aryl bromides.
EXAMPLES 32-34
The catalyst X.sub.n M(ER.sub.1-4).sub.m may also be a chiral catalyst. In
this case one can use a non-racemic chiral catalyst to generate
non-racemic products. This asymmetric version of the reaction is evidenced
by the optical activity of the purified .alpha.-arylketone products (Table
IV).
TABLE IV
__________________________________________________________________________
Optical
Example
ArX Substrate Catalyst Rotation
__________________________________________________________________________
32 PhBr
##STR42##
##STR43## [.alpha.].sub.D.sup.20 = 8.4 (c =
1.00, CHCl.sub.3)
33 PhBr
##STR44##
##STR45## [.alpha.].sub.D.sup.20 = -3.2 (c =
1.00, CHCl.sub.3)
34 PhBr
##STR46##
##STR47## [.alpha.].sub.D.sup.20 = 0.5 (c =
1.00, CHCl.sub.3)
__________________________________________________________________________
While the invention has been described above with reference to specific
embodiments thereof, it is apparent that many changes, modifications, and
variations can be made without departing from the inventive concept
disclosed herein. Accordingly, it is intended to embrace all such changes,
modifications, and variations that fall within the spirit and broad scope
of the appended claims. All patent applications, patents, and other
publications cited herein are incorporated by reference in their entirety.
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